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Cracking the Puzzle of the ‘Mother of All Molecules’: A Conversation with Venki Ramakrishnan

Cracking the Puzzle of the ‘Mother of All Molecules’: A Conversation with Venki Ramakrishnan

For his pioneering work on ribosomes, Venkatraman Ramakrishnan won the Nobel Prize in Chemistry in 2009.

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How is genetic information translated into chains of amino acids which combine to form proteins, the building blocks of life?

In the ‘Gene Machine’, published by Harper Collins India, Nobel Laureate and the President of the Royal Society Venkatraman Ramakrishnan – better known as Venki Ramakrishnan – answers this fundamental question in biology.

Along with that, he chronicles the behind-the-scenes drama that led to the unraveling of the structure and function of the ribosome, the molecule responsible for making proteins in all living organisms.

Photo: Karthik Ramaswamy

For his pioneering work, he won the Nobel Prize in Chemistry in 2009, an award he shared with the Israeli crystallographer Ada Yonath and the American biochemist Thomas Steitz.

In a brief sit-down during his visit to IISc, Ramakrishnan tells us about the book, the strange business of being a Nobel Laureate in India, what scientists are really like, and why the ribosome structure was so hard to crack.

Give us an elevator pitch for why you think people should read ‘Gene Machine’.

I would say in one go you’ll learn about the mother of all molecules – the molecule that makes everything else in the cell or makes molecules that make everything else. At the same time, you’ll get an inside look into how science works and what scientists are really like.

The theme of you as an outsider crops up several times in the book: an Indian who went to the west to make a career and a physicist who stumbled upon biochemistry. What’s been the biggest handicap and what’s been the biggest advantage for you as an outsider – a cultural and an academic outsider?

I think [being] an outsider allows you to see things with a fresh perspective that isn’t obvious to people who are either part of the culture or part of the field. They are used to thinking in a certain way. And you come in there and say, “Wait a minute. Why is everybody doing it like this?” When people come in from a different field or different country, they bring a new perspective sometimes. That’s why I’m a big fan of people moving around in science. Science often benefits from this global [churn].

But I wouldn’t say I was too much of an outsider in biology. If you remember from the book, I actually went back to graduate school in biology and I even took undergraduate courses. So it was not as if I wandered into a biology lab and didn’t know anything. I made a deliberate decision not to just do a postdoc in biology [immediately after finishing my Ph.D. in physics]. Then I really would’ve been an outsider and would’ve learned a narrow part of biology. But I wanted to get a proper background.

That’s why I’m a big fan of people moving around in science

Like many immigrants, you saw America as the Promised Land. Would that also be a useful metaphor to describe the field of molecular biology in the 1970s when you decided to switch from physics?

The field was flourishing and new discoveries were constantly being made. What do you mean by Promised Land? What you mean is lots of opportunities. So in that sense, you’re right. In a way, molecular biology was a Promised Land as well.

The book is written almost like a thriller involving a race with fierce competitors where the personal story is interwoven with the scientific story. That’s not the most obvious way to write a popular science book. Why did you choose this narrative? And when did you arrive at it – was it something you always wanted to do or did it evolve?

I realised that this – the ribosome story – had an interesting human drama about it because of the way it evolved and the people [in it] and so on. Even while it was happening, I said [to myself] that this is going to make a good story someday.

I was also very influenced by The Double Helix by Jim Watson. I read it as an undergraduate in Baroda (now Vadodara). At the time I was a physicist and biology was taught as a collection of facts to be memorised. The Double Helix for the first time gave me a feeling that biology was actually very interesting. There were goals.

There was a mystery and you could go solve it. It’s not just about collecting a bunch of facts. It was written in a very personal style. Again as you say, it wove the science with the personal stuff. And it was written very frankly. I thought it would be good to write in that genre.

Of course, there’s a fine line between being very, very frank and honest and being what I would call unnecessarily nasty. I would like to think that I’m on this side of that line and not on the nasty side.

The Double Helix for the first time gave me a feeling that biology was actually very interesting.

One of the takeaways from the story of the discovery of the structure of the ribosome and how it works is that scientific progress is non-linear. But research papers and textbooks give us a sanitised version of the process. So how does one get the political establishment and society to appreciate the messiness of the scientific process?

Well, that’s one reason I wrote the book – to educate the general public which hopefully will include decision makers. The former Science Minister in Britain has read my book and liked it. People in all walks of life need to understand how science is done. What is the process of science like? How do discoveries emerge?

It’s not like turning on a tap and discoveries flow out. It’s more like planting seeds. That would be a better analogy. You plant seeds, you nurture it. Some of the seeds will flourish and become great big trees. Others may not. But if you don’t plant widely, you’re not going to get anything. That’s the way I would look at it.

You don’t shy away from referring to your own insecurities, apprehensions, and also the occasional embarrassment. While you laud the vision of Ada Yonath, your main competitor with whom you shared the Nobel Prize, you are also critical of her in some instances.

Richard Dawkins says you write with “disarming frankness”. How hard was it to be brutally honest about yourself and your competitors when you were writing it? Did you think of editing some sections out at any point?

Dawkins also calls me a “nice Jim Watson”!

Some parts have been edited because the book has been carefully checked by lawyers. But even after the editing, it conveys the sense that the original draft had. Again The Double Helix was sort of a model. My view is that you want to tell people what science is like, what scientists are like, and how it felt [being part of the race]. If not, why would you want to write a book?

If you’re not going to be honest, the reader is not going to have a true picture. So it’s almost imperative to be completely honest. If you’re worried about it, you shouldn’t be writing it. Or you could write some other book.

You talk about the politics of recognition and warn against the corrupting influence that awards can have on researchers. You’ve even coined a term Nobelitis – both pre- and post- Nobelitis – that afflicts many scientists. How did you deal with it when it seemed like the carrot was dangling in front of you and after you received the Nobel Prize?

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I go through that in the book. I think it’s very, very hard. When you first go after a problem, you’re not thinking of awards. You’re thinking that this is the most important problem in the field. And I want to take a stab at cracking it. Soon you find yourself in the middle of a race. And then the problem is solved. You’re happy, you’re ecstatic that [the solution to] this very tough problem has actually been worked out. The gamble has paid off. Then what happens is that you go to meetings and conferences. And you go give seminars at top universities.

After your talk or at dinner people say, “You know… this is going to get a Nobel Prize someday.” And then it starts to slowly warp your thinking: “Maybe it is [true]. All these people are telling me. Not just my good friend who is not objective. All sorts of people are telling me about this.” You start getting invited to meetings in Sweden and for other keynote talks and so on.

Suddenly it affects your psychology. You start thinking, “Do I have a chance or don’t I? Who else would be in the running? Oh, maybe I’m not good enough.” It’s not a good feeling.

I talk in the book about how after one meeting in Sweden, I basically decided that I wasn’t going to be in the running for one funny reason. Somebody with whom I had a disagreement ended up on the [Nobel] committee. [I thought] that settles that. In a way the moment I decided I didn’t have a chance it was a huge relief. Because then I could go back to my old self and keep enjoying science for its sake and watch the other people worry about it.

Photo: Nithyanand Rao

And after you won the Nobel Prize…

I didn’t expect that level of press and public recognition although oddly Britain was the one place where I was hardly recognised. None of the TV stations featured me on their newscast. I wasn’t in the print edition of most of the British newspapers.

You would’ve thought that the fact that somebody from the US took a salary cut to come and do science in Britain would’ve made a great story for British science and for Britain. It was a little odd.

But the business from India was really strange because I’d left India when I was 19. I had almost nothing to do with Indian science except that I started coming to Bengaluru and a few other places from about 2006.

So the people who knew me in India were people in my field: molecular and structural biology. They knew my work. Nobody else cared about it. At all. I gave a lecture in honour of GN Ramachandran in 2008 in Chennai. The hall was maybe half full.

The next year a hall that was about three times as big was packed. What was the difference between 2008 and 2009? My work hadn’t changed.

So I think it’s a very strange business. And I talk in the book about [the fact that] people don’t understand what the Nobel is. It’s given for advancing a field by making a discovery or invention. But it does not mean that you’re a genius. It doesn’t even mean that you’re very smart. There are Nobel Laureates who simply got lucky. They weren’t great scientists even. I think it’s a bit odd. I’ve learned to go with the flow and try not to let it disrupt my life too much.

It [the Nobel Prize] is given for advancing a field by making a discovery or invention. But it does not mean that you’re a genius. It doesn’t even mean that you’re very smart

When did you realise that you wanted to write this book? Or did you want to write a book and then decided that it was going to be this one?

It was this book. And it was gestating even before the Nobel Prize. Because as I said, [even] as events unfolded, this would make a great story. Soon after the Nobel, I started collecting material for the book and interviewing people.

In fact, some of the people I talked to are dead now. So it’s a good thing I interviewed them a long time ago. And then I thought this has been going on long enough.

Alex [Alexander] Gann at Cold Spring Harbor Lab, a very fine scientist and also a science writer – he edited the annotated version of The Double Helix – said, “You really should be writing this.” He’s been encouraging me all along. The last time I met him, he said, “Look, years have gone by. If you publish one more Nature paper, not many are going to read it. But if you write this book, you’re going to reach thousands of people. Not just half a dozen people who are going to read your paper in depth.”

So I thought at some point it’s worth sitting down and actually doing it. And once I found an agent, there really was the pressure to start writing it.

Structure and shape of the E.coli 70S ribosome. The large 50S ribosomal subunit (red) and small 30S ribosomal subunit (blue) are shown with a 200 Ångstrom (20 nm) scale bar (Image credit: Vossman/Wikimedia Commons, CC BY-SA 3.0)

The ribosome, as you put it, lies at the crossroads of life itself because it forms the crucial link between genes and proteins. But after the discovery of the double helix, it’s taken several decades for us to understand the ribosome and how it works. Is it merely because of the complexity of the molecule?

Yes. DNA, by contrast, is a very simple molecule – it has a simple double helix. It has a very symmetric structure, a very regular structure. You can think of it as a very simple coil, whereas you can think of the ribosome as a big mass of spaghetti. So it is a very complicated and enormous structure. I think it’s probably why it took so long.

You can think of it [DNA molecule] as a very simple coil, whereas you can think of the ribosome as a big mass of spaghetti.

The ribosome was always a target, but people just didn’t think it couldn’t be done. To their credit, Ada Yonath and Heinz-Günter Wittmann (a German biochemist at the Max Planck Institute) got the first crystals. Ada had the vision that this is the way forward. We didn’t know how to do it, but this is the way forward. Other people thought, “Why should we do it? She’s got crystals and a huge group. What’s the point in competing with her?” I think there was some feeling about that as well. Otherwise, other groups might have joined in earlier.

This republished interview was conducted jointly for Connect, IISc’s magazine, and by Karthik Ramaswamy.

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